Alcohol-use disorders create a huge global health care burden, which ranks number two in the mental, neurological and substance-use disorders, indicating an urgent need for more effective treatments. It is well known that alcohol-use is very different from other drugs of abuse such as cocaine in multiple aspects: whereas some individuals drink alcohol for decades in a controlled manner and without developing dependence, others have an uncontrollable desire to drink and develop severe alcohol addiction. To understand the neurophysiological mechanisms that underlie the evidently different drinking behaviors, we hypothesize that there is alcohol drinking variability even in genetically identical inbred mice. This hypothesis is important because previous efforts to understand the drinking variations in animal models have encountered huge challenges, which is in part induced by the variable gene backgrounds and the unknown complex interactions between genes and the environment. In our preliminary studies toward testing this hypothesis, we observed that in C57BL/6J mice, an inbred strain typically used in alcohol research because of its high ad libitum consumption of alcohol, roughly 10% had lower alcohol drinking behaviors (preference and consumption). This provides us with an exceptional experimental model to explore the individual variations in alcohol drinking behaviors. To investigate the neurophysiological basis underlying variable alcohol drinking behaviors, we focus on the brain's reward circuit, a well-known neural system that is critically involved in mediating natural reward and drug reinforcement. We propose to: (1) characterize the differences in the firing activity of ventral tegmental area (VTA) dopamine neurons in low and high alcohol drinking mice, and, more specifically, of the subpopulations of VTA neurons projecting to the nucleus accumbens (NAc), medial prefrontal cortex (mPFC) and amygdala (BLA); (2) optogenetically dissect the functional roles of VTA dopamine neurons and their specific projections to NAc, mPFC and BLA in mediating the variable alcohol drinking behaviors; (3) intensively explore the ion channel and receptor mechanisms underlying the differences in the firing properties of VTA dopamine neurons and projection-specific neurons in the VTA to identify possible novel drug targets. In this project, we will provide the direct causal links between alcohol drinking behaviors and the specific roles of firing patterns, cell types and neural circuits via the combined use of state-of-the-art electrophysiological and sophisticated optogenetic approaches in freely behaving mice. These proposed molecular, cellular and neural circuit studies will provide very useful and highly novel information, both for improving our knowledge of variable alcohol drinking behaviors and for identifying new drug targets to develop more effective, individualized treatments for alcohol-use disorders.